Calcilytic compounds

ABSTRACT

Novel calcilytic compounds and methods of using them are provided.

This application is a continuation of U.S. application Ser. No.13/764,126 filed Feb. 11, 2013, which is a continuation of U.S.application Ser. No. 12/894,644 filed Sep. 30, 2010, which is acontinuation of U.S. application Ser. No. 12/393,284 filed Feb. 26,2009, which is a divisional of U.S. application Ser. No. 10/536,416,filed 25 May 2005, which is a 371 application of PCT/US2003/037461 filed25 Nov. 2003 which claims the benefit of U.S. Provisional ApplicationNo. 60/429,105, filed 26 Nov. 2002.

FIELD OF INVENTION

The present invention relates novel compounds able to inhibit calciumreceptor activity and the use of such compounds. Preferably, thecompounds described herein are administered to patients to achieve atherapeutic effect.

BACKGROUND OF THE INVENTION

The present invention relates to novel calcilytic compounds,pharmaceutical compositions containing these compounds and their use ascalcium receptor antagonists.

In mammals, extracellular Ca²⁺ is under rigid homeostatic control andregulates various processes such as blood clotting, nerve and muscleexcitability, and proper bone formation. Extracellular Ca²⁺ inhibits thesecretion of parathyroid hormone (“PTH”) from parathyroid cells,inhibits bone resorption by osteoclasts, and stimulates secretion ofcalcitonin from C-cells. Calcium receptor proteins enable certainspecialized cells to respond to changes in extracellular Ca²⁺concentration.

PTH is the principal endocrine factor regulating Ca²⁺ homeostasis in theblood and extracellular fluids. PTH, by acting on bone and kidney cells,increases the level of Ca²⁺ in the blood. This increase in extracellularCa²⁺ then acts as a negative feedback signal, depressing PTH secretion.The reciprocal relationship between extracellular Ca²⁺ and PTH secretionforms an important mechanism maintaining bodily Ca²⁺ homeostasis.

Extracellular Ca²⁺ acts directly on parathyroid cells to regulate PTHsecretion. The existence of a parathyroid cell surface protein whichdetects changes in extracellular Ca²⁺ has been confirmed. See Brown etal., Nature 366:574, 1993. In parathyroid cells, this protein, thecalcium receptor, acts as a receptor for extracellular Ca²⁺, detectschanges in the ion concentration of extracellular Ca²⁺, and initiates afunctional cellular response, PTH secretion.

Extracellular Ca²⁺ influences various cell functions, reviewed in Nemethet al., Cell Calcium 11:319, 1990. For example, extracellular Ca²⁺ playsa role in parafollicular (C-cells) and parathyroid cells. See Nemeth,Cell Calcium 11:323, 1990. The role of extracellular Ca²⁺ on boneosteoclasts has also been studied. See Zaidi, Bioscience Reports 10:493,1990.

Various compounds are known to mimic the effects of extra-cellular Ca²⁺on a calcium receptor molecule. Calcilytics are compounds able toinhibit calcium receptor activity, thereby causing a decrease in one ormore calcium receptor activities evoked by extracellular Ca²⁺.Calcilytics are useful as lead molecules in the discovery, development,design, modification and/or construction of useful calcium modulators,which are active at Ca²⁺ receptors. Such calcilytics are useful in thetreatment of various disease states characterized by abnormal levels ofone or more components, e.g., polypeptides such as hormones, enzymes orgrowth factors, the expression and/or secretion of which is regulated oraffected by activity at one or more Ca²⁺ receptors. Target diseases ordisorders for calcilytic compounds include diseases involving abnormalbone and mineral homeostasis.

Abnormal calcium homeostasis is characterized by one or more of thefollowing activities: an abnormal increase or decrease in serum calcium;an abnormal increase or decrease in urinary excretion of calcium; anabnormal increase or decrease in bone calcium levels (for example, asassessed by bone mineral density measurements); an abnormal absorptionof dietary calcium; an abnormal increase or decrease in the productionand/or release of messengers which affect serum calcium levels such asPTH and calcitonin; and an abnormal change in the response elicited bymessengers which affect serum calcium levels.

Thus, calcium receptor antagonists offer a unique approach towards thepharmacotherapy of diseases associated with abnormal bone or mineralhomeostasis, such as hypoparathyroidism, osteosarcoma, periodontaldisease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget'sdisease, humoral hypercalcemia associated with malignancy and fracturehealing, and osteoporosis.

SUMMARY OF THE INVENTION

The present invention features calcilytic compounds. “Calcilyticcompounds” refer to compounds able to inhibit calcium receptor activity.The ability of a compound to “inhibit calcium receptor activity” meansthat the compound causes a decrease in one or more calcium receptoractivities evoked by extracellular Ca²⁺.

The use of calcilytic compounds to inhibit calcium receptor activityand/or achieve a beneficial effect in a patient is described below. Alsodescribed below are techniques which can be used to obtain additionalcalcilytic compounds.

An example of featured calcilytic compounds are Structure I having thechemical formula:

wherein:

-   -   R₁ and R₅ are independently selected from the group consisting        of H and halogen    -   R₂, R₃ and R₄ are independently selected from the group        consisting of H, halogen and J-K wherein:        -   J is a covalent bond, alkylene or alkenyl: and K is selected            from the group of CO₂R₈, such that R₈ is H or alkyl    -   R₆ is selected from the group consisting of H or alkyl    -   R₇ is selected from the group consisting of aryl or fused aryl,        dihydro, tetrahydro fused aryl, heteroaryl, unsubstituted or        substituted with any substituent selected from the group        consisting of OH, halogen, C_(1-4 alkyl), C_(1-4alkoxy),        C_(3-6 cycloalkyl), CF₃, OCF₃, CN and NO₂,

and pharmaceutically acceptable salts and complexes thereof.

“Alk” refers to either alkyl or alkenyl. “Lower alk” refers to eitherlower alkyl or lower alkenyl, preferably lower alkyl.

“Alkenyl” refers to an optionally substituted hydrocarbon groupcontaining at least one carbon-carbon double bond between the carbonatoms and containing 2-6 carbon atoms joined together. The alkenylhydrocarbon group may be straight-chain. Straight-chain alkenylpreferably has 2 to 4 carbons.

“Alkyl” refers to an optionally substituted hydrocarbon group joined bysingle carbon-carbon bonds and having 1 to 6 carbon atoms joinedtogether. The alkyl hydrocarbon group may be straight-chain or containone or more branches. Branched- and straight-chain alkyl preferably have1 to 4 carbons, each of which may be optionally substituted. Alkylsubstituents are each independently selected from the group consistingof: lower alkyl, unsubstituted aryl, OH, NH₂, NH-lower alkyl, andN(lower alkyl)₂. Preferably, no more than two substituents are present.Even more preferably, alkyl is a lower alkyl which is unsubstitutedbranched- or straight-chain alkyl having 2 to 4 carbons.

“Aryl” refers to an optionally substituted aromatic group with at leastone ring having a conjugated or fused ring systems. Aryl includescarbocyclic aryl, heterocyclic aryl and biaryl groups, all of which maybe optionally substituted. Preferably, the aryl is either optionallysubstituted phenyl or optionally substituted pyridyl.

“Alkoxy” refers to oxygen joined to an unsubstituted alkyl 1 to 4 carbonatoms in length, preferably 1 to 2 carbons in length. More preferably,the alkoxy is methoxy.

Preferred compounds useful in the present invention are selected fromthe group consisting of:

-   3-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-acrylic    acid hydrochloride;-   3-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic    acid hydrochloride;-   3-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic    acid ethyl ester hydrochloride;-   (E)-3-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pent-4-enoic    acid hydrochloride;-   5-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pentanoic    acid hydrochloride;-   5-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pentanoic    acid ethyl ester;-   3-{4-Bromo-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic    acid ethyl ester hydrochloride;-   3-{4-Bromo-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic    acid hydrochloride;-   3-{2,3-Difluoro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic    acid hydrochloride;-   3-{2,3-Difluoro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic    acid ethyl ester hydrochloride;-   (E)-3-{2,3-Dichloro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-acrylic    acid hydrochloride;-   3-{2,3-Chloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic    acid hydrochloride;-   3-{2,3-Chloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic    acid ethyl ester trifluoroacetate;-   3-{4-Fluoro-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic    acid ethyl ester hydrochloride;-   3-{4-Fluoro-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic    acid hydrochloride;-   3-{2-Chloro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic    acid ethyl ester hydrochloride;-   3-{2-Chloro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic    acid hydrochloride;-   3-{2,4-Dichloro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic    acid ethyl ester;-   5-{2,3-Dichloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pentanoic    acid trifluoroacetate;-   5-{2,3-Dichloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pentanoic    acid ethyl ester trifluoroacetate;-   3-{2,3-Dichloro-4-[2-(R)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(R)-methyl-propoxy]-phenyl    propionic acid ethyl ester hydrochloride;-   3-{2,3-Dichloro-4-[2-(S)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethyl    amino)-1(S)-methyl-propoxy]-phenyl propionic acid ethyl ester    hydrochloride;-   {2,3-Dichloro-4-[2-(R)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethyl    amino)-1(S)-methyl-propoxy]-phenyl propionic acid ethyl ester    hydrochloride;-   3-{2,3-Dichloro-4-[2-(S)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethyl    amino)-1(R)-methyl-propoxy]-phenyl propionic acid ethyl ester    hydrochloride;-   3-{2,3-Dichloro-4-[2-(R)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethyl    amino)-1(R)-methyl-propoxy]-phenyl propionic acid hydrochloride;-   3-{2,3-Dichloro-4-[2-(S)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethyl    amino)-1(S)-methyl-propoxy]-phenyl propionic acid hydrochloride;-   3-{2,3-Dichloro-4-[2(-R)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethyl    amino)-1(S)-methyl-propoxy]-phenyl propionic acid hydrochloride;-   3-{2,3-Dichloro-4-[2-(S)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethyl    amino)-1(R)-methyl-propoxy]-phenyl propionic acid hydrochloride;-   3-{3-Chloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic    acid ethyl ester;-   3-{3-Chloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic    acid;-   3-{3-Bromo-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic    acid ethyl ester;-   3-{3-Bromo-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic    acid;-   3-{3-[(R)-2-Hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic    acid ethyl ester;-   3-{3-[(R)-2-Hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic    acid; and-   3-{4-[(R)-2-Hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic    acid.

DETAILED DESCRIPTION OF THE INVENTION

The present application demonstrates the ability of calcilytic compoundsto exert a physiologically relevant effect on a cell by illustrating theability of such compounds to increase PTH secretion and also identifiesa target site for calcilytic compounds.

wherein:

-   -   R₁ and R₅ are independently selected from the group consisting        of H and halogen    -   R₂, R₃ and R₄ are independently selected from the group        consisting of H, halogen and J-K wherein:        -   J is a covalent bond, alkylene or alkenyl: and K is selected            from the group of CO₂R₈, such that R₈ is H or alkyl    -   R₆ is selected from the group consisting of H or alkyl    -   R₇ is selected from the group consisting of aryl or fused aryl,        dihydro, tetrahydro fused aryl, heteroaryl, unsubstituted or        substituted with any substituent selected from the group        consisting of OH, halogen, C_(1-4 alkyl), C_(1-4alkoxy),        C_(3-6 cycloalkyl), CF₃, OCF₃, CN and NO₂,        and pharmaceutically acceptable salts and complexes thereof.

Synthesis Schemes.

The synthesis of the compounds of the general formula (I) may beprepared as outlined below in Schemes 1 and 2. Treatment of the phenol 1with a base such as potassium carbonate in the presence of the nosylepoxide 2 provides the epoxide intermediate 3. Treatment of 3 with anamine such as 4 in a solvent such as ethanol at elevated temperatureprovides the aminoalcohol 5. Heck coupling of 5 with an olefin such asethyl acrylate provides the α,β-unsaturated ester 6 which is saponifiedwith a base such as sodium hydroxide in ethanol and water to provide theacrylic aid derivative 7. The acrylic acid 7 is reduced under conditionswhich are common to the art such as hydrogen in the presence of acatalyst such as palladium on carbon to provide the acid 8 which isesterified under conditions common to the art to provide the ester 9.

As shown in Scheme 2 compounds of the general formula (I) may beprepared by halogenation of a phenol such as3-(3-hydroxy-phenyl)-propionic acid ethyl ester 10 to provide3-(4-bromo-3-hydroxy-phenyl)-propionic acid ethyl ester 11. The ester 11may be converted to the epoxide 12 as described above. Epoxide 12 can beconverted to the acid/ester pair 13 and 14 as described above for thesynthesis of 8 and 9.

Experimental Procedures

The following examples are intended to be merely illustrative of thepresent invention and not limiting in any way.

Example 1 Preparation of(E)-3-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-acrylicacid hydrochloride (a)(R)-2-(5-Bromo-2,3-difluoro-phenoxymethyl)-oxirane

To an acetone solution (0.1 M, 240 mL) of commercially available5-bromo-2,3-difluorophenol (5.0 g, 23.93 mmol) was added K₂CO₃ (9.92 g,71.77 mmol), and the mixture was heated to reflux for 30 min. Aftercooling this mixture to RT, (2R)-(−)-glycidyl 3-nitrobenzenesulfonate(6.20 g, 23.93 mmol) was added, and the resulting mixture was heated toreflux overnight. After cooling to RT, the solids were removed byfiltration and washed well with ethyl acetate. The filtrate wasconcentrated and partitioned between ethyl acetate and 1N HCl. Theorganic portion was washed successively with 5% NaHCO₃ and brine, dried(MgSO₄), filtered and concentrated to a solid. Purification by FCC (15%ethyl acetate/hexanes) gave the product as a white solid in 97% yield(6.19 g).

(b)(R)-1-(5-Bromo-2,3-difluoro-phenoxy)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propan-2-ol

An ethanolic solution (0.2 M, 93 mL) of the oxirane of Example 1a (5 g,18.67 mmol) and 2-indan-2-yl-1,1-dimethyl-ethylamine (free base, 3.57 g,18.67 mmol) was heated to refux for 12 h. After solvent removal, thecrude reaction mixture was purified by FCC (5% CH₃OH/CH₂Cl₂) to givepure product as a yellow oil (solidifies on standing) in 84% yield (7.1g). ¹H NMR (dmso-d₆): δ 9.05 (t, J=9.0 Hz, 1H); 8.65 (t, J=9.0 Hz, 1H);7.40 (ddd, J=9.75, 6.4, 2.2 Hz, 1H); 7.34 (ddd, J=6.7, 2.0, 2.0 Hz, 1H);7.18 (m, 2H); 7.10 (m, 2H); 6.0 (d, J=4.8 Hz, 1H); 4.25 (m, 1H); 4.20(m, 2H); 3.17 (m, 1H); 3.08 (m, 2H); 2.95 (m, 1H); 2.58 (m, 3H); 1.97(d, J=5.43 Hz, 2H); 1.39 (s, 6H).

LCMS (m/z) M+H=454/456.

(c)(E)-3-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-acrylicacid hydrochloride

To a solution of the bromide of Example 1b (21.0 g, 46.26 mmol) indegassed propionitrile (0.2 M, 230 mL) were added Pd(OAc)₂ (0.52 g, 2.31mmol), P(o-tol)₃ (2.11 g, 6.94 mmol), DIPEA (17.7 mL, 101.76 mmol), andethyl acrylate (6.51 mL, 60.13 mmol). The reaction flask was fitted witha condenser, kept under Ar cover, and placed in a pre-heated bath (115°C.) for 3.5 h. After cooling to RT, the reaction mixture was filteredthrough Celite, and the filtrate was concentrated, partitioned betweenethyl acetate and 1N HCl. The layers were separated and the organicportion was washed successively with 5% NaHCO₃ and brine, dried (MgSO₄),filtered and concentrated to a brown oil.

A portion of the crude residue (6.2 g) was brought up in ethanol andwater (0.2 M, 50 mL, 13 mL) and treated with 2N NaOH (13 mL). Thereaction mixture stirred at RT for 12 h. The ethanol was removed and theaqueous portion (pH 14) was diluted up to 200 mL and extracted 3× with30 mL portions of diethyl ether. Aqueous HCl was added while stirring toadjust the pH to 5, causing the product come out of solution as a gum.CH₂Cl_(2 was added, and the biphasic mixture was stirred well for) 5-30min. By this method, the product was transformed into a white solid andwas isolated as pure zwitterion by filtration (3.3 g, 70% for 2 steps).

To an acetonitrile suspension of the zwitterion product was added 2M HClin diethyl ether. The material briefly went into solution, and thenprecipitated as a white crystalline solid to give(E)-3-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-acrylicacid as the pure HCl salt. ¹H NMR (dmso-d₆): δ 12.53 (s, 1H); 8.91 (m,1H); 8.58 (m, 1H); 7.54 (d, J=16.0 Hz, 1H); 7.49 (m, 2H); 7.18 (m, 2H);7.11 (m, 2H); 6.67 (d, J=16.0 Hz, 1H); 6.0 (d, J=4.4 Hz, 1H); 4.27 (m,1H); 4.23 (m, 2H); 3.17 (m, 1H); 3.09 (dd, J=13.4, 7.05 Hz, 2H); 2.96(m, 1H); 2.56 (m, 3H); 1.96 (d, J=5.4 Hz, 2H); 1.39 (s, 6H).

Example 2 Preparation of3-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid hydrochloride

To a solution of the acrylic acid of Example 1 (2.5 g, 5.62 mmol) inacetic acid (30 mL) and ethyl acetate (20 mL) was added 5% Pd/CaCO₃(0.50 g). The reaction flask was purged with H₂ and sealed under a H₂balloon for 15 h. The mixture was filtered through Celite, and thefiltrate was concentrated to approx 5 mL volume. Toluene (100 mL) and 2MHCl in diethyl ether (10 mL) were added and the solution wasconcentrated to a white solid.

The solid was suspended in acetonitrile and treated with 2M HCl indiethyl ether. This solution was concentrated to dryness providing thetitle compound as the HCl salt as a white solid: ¹H NMR (dmso-d₆): δ 9.0(m, 1H); 8.6 (m, 1H); 7.19 (m, 2H); 7.11 (m, 2H); 6.98 (app. d, J=7.1Hz, 1H); 6.91 (m, 1H); 6.0 (br s, 1H); 4.27 (m, 1H); 4.14 (d, J=5.1 Hz,2H); 3.20 (m, 1H); 3.10 (m, 2H); 2.98 (m, 1H); 2.79 (t, J=7.7 Hz, 2H);2.58 (m, 5H); 1.97 (d, J=5.4 Hz, 2H); 1.39 (s, 6H): LCMS (m/z) M+H=448.

Example 3 Preparation of3-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester hydrochloride

To a suspension of the propionic acid of Example 2 (2 g) in ethanol (20mL) was added 2M HCl in diethyl ether (2 mL). The mixture was heated toreflux for 3 h. After cooling to RT, the resulting solution wasconcentrated to a yellow oil and dried under vacuum. The contents of theflask solidified to give the title compound as an HCl salt (2 g): ¹H NMR(dmso-d₆): δ 9.05 (m, 1H); 8.62 (m, 1H); 7.18 (m, 2H); 7.11 (m, 2H);6.98 (app. d, J=7.1 Hz, 1H); 6.91 (m, 1H); 6.0 (br s, 1H); 4.27 (m, 1H);4.14 (d, J=5.2 Hz, 2H); 4.06 (q, J=7.1 Hz, 2H); 3.18 (m, 1H); 3.09 (m,2H); 2.98 (m, 1H); 2.82 (t, J=7.5 Hz, 2H); 2.61 (m, 5H); 1.97 (d, J=5.4Hz, 2H); 1.39 (s, 6H); 1.17 (t, J=7.1 Hz, 3H): LCMS (m/z) M+H=476.

Example 4 Preparation of5-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pentanoicacid hydrochloride

The title compound was prepared in two steps by the methods describedabove for the preparation of the compound of Example 1 except thatethyl-4-pentenoate was used instead of ethyl acrylate in the Heckcoupling reaction to provide5-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pent-4-enoicacid ethyl ester. The ethyl ester product of the Heck reaction washydrolyzed to the carboxylic acid in a manner similar to that describedabove. HCl salt formation was carried out by the method described above:¹H NMR (dmso-d₆): δ 8.9 (br, 1H); 8.55 (br, 1H); 7.18 (m, 2H); 7.07 (m,5H); 6.38 (s, 1H); 5.99 (br s, 1H); 4.25 (m, 1H); 4.15 (m, 2H); 3.36 (m,2H); 3.19 (m, 1H); 3.08 (dd, J=13.3, 7.05 Hz, 2H); 2.95 (m, 1H); 2.55(m, 3H); 2.40 (s, 2H); 1.95 (d, J=5.3 Hz, 2H); 1.39 (s, 6H): LCMS (m/z)M+H=474.6.

Example 5 Preparation of5-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pentanoicacid

The title acid was prepared by hydrogenation in the presence ofcatalytic Pd/CaCO₃ in acetic acid and ethyl acetate in a manner similarto that described above in Example 2:

¹H NMR (dmso-d₆): δ 8.75 (m, 1H); 8.50 (m, 1H); 7.19 (m, 2H); 7.10 (m,2H); 6.90 (m, 2H); 5.95 (d, J=4.3 Hz, 1H); 4.22 (m, 1H); 4.15 (m, 2H);3.4 (m, 2H); 3.20 (m, 1H); 3.10 (dd, J=13.8, 7.2 Hz, 2H); 2.98 (m, 1H);2.60 (m, 3H); 2.24 (t, J=7.2 Hz, 2H); 1.95 (d, J=5.7 Hz, 2H); 1.56 (m,2H); 1.51 (m, 2H), 1.38 (s, 6H): LCMS (m/z) M+H=476.

Example 6 Preparation of5-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pentanoicacid ethyl ester

To a solution of5-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pent-4-enoicacid ethyl ester of Example 4 (12.0 g, 23.95 mmol) in ethanol (250 mL)was added 5% Pd/CaCO₃ (2.4 g). The reaction flask was purged with H₂ andsealed under a H₂ balloon for 15 h. The mixture was filtered throughCelite, and the filtrate was concentrated. Column chromatography of theresidue (SiO₂, 5% CH₃OH/CH₂Cl₂) provided pure ester product, which wasconverted to the HCl salt using the method described above.

Example 7 Preparation of3-{4-Bromo-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester hydrochloride (a) 3-(3-Hydroxy-phenyl)-propionic acidethyl ester

To a solution of commercially available 3-(3-hydroxy-phenyl)-propionicacid (25 g, 150.4 mmol) in ethanol (250 mL) was added concentratedsulfuric acid (3.0 mL). The solution was heated to reflux overnight. Thesolvent was removed in vacuo, and the resulting oil was diluted ethylacetate and placed in a separatory funnel. The organic portion wasextracted 2× with 5% NaHCO₃ and once with brine. The solution was dried(MgSO₄), filtered and concentrated to a dark tan oil (30 g). Thismaterial was carried on to the next step without further purification.

(b) 3-(4-Bromo-3-hydroxy-phenyl)-propionic acid ethyl ester

To a −10° C. solution of 3-(3-hydroxy-phenyl)-propionic acid ethyl ester(2.0 g, 10.31 mmol) in chloroform (0.2 M, 51 mL) was addedN-bromosuccinimide (1.93 g, 10.83 mmol). After stirring at RT overnight,the solution was concentrated in vacuo and purified by flash columnchromatography (SiO2, 5% to 15% ethyl acetate/hexanes) to give theproduct as a colorless oil (0.45 g, 16%).

(c) R)-2-(5-Bromo-2,3-difluoro-phenoxymethyl)-oxirane

A suspension of 3-(4-bromo-3-hydroxy-phenyl)-propionic acid ethyl ester(0.6 g, 2.20 mmol) and K₂CO₃ (0.91 g, 6.59 mmol) in acetone (0.1 M, 22mL) was heated to reflux for 30 min. After cooling this mixture to RT,(2R)-(−)-glycidyl 3-nitrobenzenesulfonate (0.57 g, 2.20 mmol) was added,and the resulting mixture was heated to reflux overnight. The solidswere removed by filtration and washed with ethyl acetate. The filtratewas concentrated and partitioned between ethyl acetate and 1N HCl. Theorganic portion was washed successively with 5% NaHCO₃ and brine, dried(MgSO₄), filtered and concentrated to a yellow oil.

(d)3-{4-Bromo-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester hydrochloride

A solution of the crude oxirane (0.7 g) and2-indan-2-yl-1,1-dimethyl-ethylamine (0.42 g, 2.2 mmol) in ethanol (0.2M, 11 mL) was heated to reflux overnight. After solvent removal, thecrude reaction mixture was purified by FCC (5% CH₃OH/CH₂Cl₂) to givepure product as a yellow oil. The material was dissolved in acetonitrileand CH₂Cl₂ and treated with 2M HCl in diethyl ether. Removal of thesolvents and drying under vacuum provided the title compound as the HClsalt as an off-white solid (0.5 g, 44% for 2 steps). ¹H NMR (dmso-d₆): δ8.70 (m, 1H); 8.52 (m, 1H); 7.47 (d, J=8.1 Hz, 1H); 7.18 (m, 2H); 7.11(m, 2H); 7.05 (d, J=1.7 Hz, 1H); 6.79 (dd, J=8.1, 1.6 Hz, 1H); 5.92 (d,J=4.7 Hz, 1H); 4.15 (m, 1H); 4.05 (q, J=7.1 Hz, 3H); 3.25 (m, 1H); 3.09(m, 3H); 2.83 (t, J=7.4 Hz, 2H); 2.64 (t, J=7.4 Hz, 2H); 2.56 (m, 3H);1.96 (d, J=5.5 Hz, 2H); 1.39 (s, 6H); 1.17 (t, J=7.1 Hz, 3H): LCMS (m/z)M+H=518/520.

Example 8 Preparation of3-{4-Bromo-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid hydrochloride

To a solution of3-{4-bromo-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester of Example 7 (0.25 g, 0.48 mmol) in ethanol (4 mL) andwater (0.8 mL) was added 2N NaOH (0.36 mL, 0.72 mmol). The solutionstirred at RT overnight. The ethanol was removed and the residue wasdiluted with water, adjusted to pH 6 and extracted 3× with CH₂Cl₂. Theorganic portion was dried (Na₂SO₄), filtered and concentrated in vacuoto give the pure zwitterion as a white solid.

To an acetonitrile suspension of the zwitterion product was added 2M HClin diethyl ether. The material briefly went into solution, and thenprecipitated as a white crystalline solid to give the pure HCl salt,which was isolated by filtration and dried under vacuum (0.18 g, 76%):¹H NMR (dmso-d₆): δ 8.80 (m, 1H); 8.55 (m, 1H); 7.47 (d, J=8.1 Hz, 1H);7.19 (m, 2H); 7.11 (m, 2H); 7.05 (d, J=1.7 Hz, 1H); 6.79 (dd, J=8.1, 1.7Hz, 1H); 5.93 (br s, 1H); 4.25 (m, 1H); 4.16 (m. 1H); 4.05 (m, 1H); 3.26(m, 1H); 3.09 (m, 3H); 2.80 (t, J=7.6 Hz, 2H); 2.62-2.52 (m, 5H); 1.96(d, J=5.4 Hz, 2H); 1.39 (s, 6H): LCMS (m/z) M+H=490/492.

Example 9 Preparation of3-{2,3-Difluoro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid hydrochloride (a) 4-bromo-2,3-difluoro-oxiranylmethoxy benzene

A solution of the crude 4-bromo-2,3-difluorophenol (0.40 g) [preparedusing published procedure, WO0121606] and (2R)-glycidyl3-nitrobenzenesulfonate (0.49 g) in dry acetone (19 mL) was treated withpotassium carbonate (0.79 g) and refluxed under nitrogen for 12 h. Thereaction was cooled, filtered and filtrate was concentrated in vacuo andthe residue was flash chomatogaphed (20% ethyl acetate/hexanes) to yieldthe desired product (0.33 g) in 71% yield. ¹H-NMR (400 MHz, CDCl₃) δ:7.23-7.19 (m, 1H), 6.74-6.71 (m, 1H), 4.35-4.32 (m, 1H), 4.03-3.99 (m,1H), 3.38-3.35 (m, 1H), 2.93-2.92 (m, 1H), 2.77-2.76 (m, 1H).

(b)(R)-1-(4-Bromo-2,3-difluorophenoxy)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propan-2-ol

A mixture of 2-(5-bromo-2,3-difluorophenoxymethyl)-oxirane of Example 8a(2.12 g, 8 mmol) and 2-indan-2-yl-1,1-dimethyl-ethylamine (1.51 g, 8mmol) were taken up in absolute ethanol (32 mL) and refluxed overnight.After all the epoxide was consumed the reaction was cooled andconcentrated and flash chromatographed (10% methanol/dichloromethane) toyield the desired product (3.06 g, 84%). MS (ES) m/z 454 (M+H)⁺.

(c)(E)-3-{2,3-Difluoro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-acrylic acid ethyl ester

A 150 mL sealed tube was charged with a stirring bar,(R)-1-(4-Bromo-2,3-difluorophenoxy)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propan-2-ol(3.06 g) 1 and propionitrile (70 mL). To this was added Pd(OAc)₂ (0.151g), P(O-tol)₃ (0.82 g), ethyl acrylate (1.35 g), triethylamine (2.73 g)sequentially and deoxygenated the reaction by bubbling nitrogen for 15minutes. The sealed tube was capped tightly and immersed into apreheated (120° C.) oil bath. The reaction was heated at thistemperature for 12 hrs. Cool to ambient temperature and concentratedunder reduced pressure. The crude residue was purified by flash columnchromatography eluting initially with 50% EtoAc in hexanes and 100%EtOAc. At this time the eluting solvent mixtures were switched to 100%dichloromethane, 5% MeOH in dichloromethane followed by 8% MeOH indichloromethane. The product was collected and concentrated to get thedesired product (2.40 g, 75%) as pale yellow foam. MS (ES) m/z 474[M+H]⁺.

(d) 3-{2,3-Difluoro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid ethyl ester

The 250 mL round bottom flask was equipped with a magnetic stir bar, thecompound of Example 8 (2.40 g), 100 mL of absolute ethanol. To this wasadded 0.24 grams (10% w/w) of catalyst (Pd/CaCO₃) and placed underhydrogen atmosphere. After 16 h of stirring all starting material wasconsumed. The reaction mixture was filtered through a pad of celite andwashed with additional amount of ethanol and concentrated to provide thecrude product (2.35 g, 98%). MS (ES) m/z 476 [M+H]⁺.

(e) 3-{2,3-Difluoro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid hydrochloride

A solution of the ester (1.6 g) in ethanol (30 mL) was treated with 2.5N NaOH (6 mL) and stirred at RT under argon overnight. The ethanol wasremoved in vacuo and the aqueous layer was diluted with water (10 mL)and then extracted with ether (3×20 mL). The aqueous layer was collectedand the pH was adjusted to pH 5 with conc.HCl while stirring. Theprecipitated white solid was collected by filtration and air dried toafford 1.3 g (86%) of a white solid: MS (ES) m/z 448 [M+H]⁺.

This acid (0.65 g) was suspended in dry acetonitrile (15 mL) and treatedwith 2.0M HCl (4 mL) in ether. The reaction mixture became homogeneousafter few minutes then a white solid crashed out. The reaction wasstirred for additional 10 minutes upon which it was filtered and driedto provide the title compound (0.52 g, 74%). MS (ES) m/z 448 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆): 8.63 (s, 1H), 8.39 (s, 1H), 7.13-6.90 (m, 6H),5.86 (d, 1H), 4.14 (brs, 1H), 4.05 (d, 2H), 3.13-3.09 (m, 1H), 3.04 and3.00 (dd, 2H), 2.93-2.89 (m, 1H), 2.75 (t, 2H), 2.55-2.44 (m, 5H), 1.89(d, 2H), 1.31 (s, 6H).

Example 10 Preparation of3-{2,3-Difluoro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid hydrochloride

The acid of Example 9 (0.65 g) was dissolved in absolute ethanol (10 mL)and catalytic amount of conc.sulfuric acid was added. The reaction wasstirred and heated to reflux overnight. The reaction was concentrated,then diluted with ethyl acetate and washed with 2.5N NaOH (2×10 mL),brine (10 mL), dried over sodium sulfate. The filtrate was concentratedand purified by HPLC and converted to the HCl salt utilizing thestandard protocol. MS (ES) m/z 476 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ8.72 (s, 1H), 8.48 (s, 1H), 7.20-6.99 (m, 6H), 5.93 (d, 1H), 4.20 (brs,1H), 4.12 (d, 2H), 4.04 (q, 2H), 3.20-3.16 (m, 1H), 3.11 and 3.07 (dd,2H), 3.00-2.96 (m, 1H), 2.85 (t, 2H), 2.62-2.51 (m, 5H), 1.95 (d, 2H),1.37 (s, 6H), 1.15 (t, 3H).

Example 11 Preparation of(E)-3-{2,3-Dichloro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-acrylicacid hydrochloride (a) 4-bromo-2,3-dichlorophenol

In a 250 mL round bottom flask 10 g of 2,3-dichlorophenol was dissolvedin a solvent mixture of glacial acetic acid (16 mL) and chloroform (4mL) and cooled to 10° C. To this was added bromine (3.45 mL) in 15 mL ofglacial acetic acid dropwise while maintaining the temperature. Thereaction was vigorously stirred while adding bromine and continuedstirring vigorously 0.5 h after addition was finished. At this timereaction mixture was poured into a flask containing 60 mL of water and30 mL of dichloromethane. Organic layer was separated and aqueous layerwas extracted with dichloromethane (3×50 mL). The oraganic layers werecombined and washed with Sat. sodium bicarbonate (3×100 mL) and brine(100 mL) and dried over sodium sulfate. The crude product (9.65 g) wascarried in to the next step without any purification. ¹H-NMR (400 MHz,CDCl₃) δ: 7.47 and 6.89 (ABq, 2H), 5.69 (brs, 1H).

(b) 4-bromo-2,3-dichloro-oxiranylmethoxy benzene

A solution of the crude 4-bromo-2,3-dichlorophenol (7.96 g) and(2R)-glycidyl 3-nitrobenzenesulfonate (8.52 g) in dry acetone (250 mL)was treated with potassium carbonate (13.61 g) and refluxed undernitrogen for 12 h. The reaction was cooled, filtered and filtrate wasconcentrated in vacuo and the residue was flash chromatographed (20%ethyl acetate/hexanes) to yield the desired product (6.94 g) in 71%yield. ¹H-NMR (400 MHz, CDCl₃) δ: 7.48 and 6.82 (d, 2H), 4.37 and 4.34(dd, 1H), 4.06 and 4.03 (dd, 1H), 3.42-3.39 (m, 1H), 2.96-2.94 (m, 1H),2.85-2.83 (m, 1H).

(c)(R)-1-(4-Bromo-2,3-dichloro-phenoxy)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propan-2-ol

A mixture of the epoxide (0.5 g) and indanyl amine (0.32 g) were takenup in absolute ethanol (16 mL) and refluxed overnight. After all theepoxide was consumed the reaction was cooled and concentrated andpurified by flash chromatography (10% methanol/dichloromethane) to yield86% of the desired product (0.71 g). MS (ES) m/e 488 [M+H]⁺.

(d)(E)-3-{2,3-Dichloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-acrylic acid ethyl ester

A 75 mL sealed tube was charged with a stir bar, the bromide (0.9 g) andpropionitrile (10 mL). To this was added Pd(OAc)₂ (0.042 g) andP(O-tol)₃ (0.23 g), ethyl acrylate (0.40 mL) sequentially anddeoxygenated the reaction by bubbling nitrogen for 15 minutes. Thesealed tube was capped tightly and immersed into a preheated (120° C.)oilbath. The reaction was heated at this temperature for 12 h. Cool toambient temperature and concentrated under reduced pressure. The cruderesidue was purified by flash column chromatography eluting initiallywith 50% EtoAc in hexanes and 100% EtoAc. At this time the elutingsolvent mixtures were switched to 100% DCM, 5% MeOH in dichloromethanefollowed by 8% MeOH in DCM. The product was collected and concentratedto get the desired product (0.95 g) in 98% yield as pale yellow foam. MS(ES) m/e 506 [M+H]⁺.

(e)(E)-3-{2,3-Dichloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-acrylic acid hyrdrochloride

A solution of the ester (5.0 g) in ethanol (49 mL) was treated with 2.5N NaOH (4.5 mL) and stirred under argon overnight. The ethanol wasremoved in vacuo and the aqueous layer was diluted with water (10 mL)and then extracted with ether (3×100 mL). The aqueous layer wascollected and the pH was adjusted to pH 4 with conc.HCl while stirring.The precipitated white solid was collected by filtration and air driedto afford the title compound (3.92 g, 83%). MS (ES) m/e 478 [M+H]⁺.¹H-NMR (400 MHz, DMSO-d₆) δ: 7.76 and 7.15 (ABQ, 2H), 7.66 (d, 1H),7.06-6.97 (m, 4H), 6.41 (d, 1H), 4.12-3.92 (m, 3H), 3.20 (brs, 1H), 2.95and 2.92 (dd, 2H), 2.84 and 2.81 (dd, 2H), 2.70 and 2.67 (dd, 2H),2.50-2.43 (m, 2H), 1.67 (d, 2H), 1.10 (s, 6H).

Example 12 Preparation of3-{2,3-Chloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid hydrochloride

A 250 mL round bottom flask was equipped with a magnetic stir bar, theacrylic acid of Example 11 (2.0 g), 100 mL of absolute ethanol and 50 mLof methanol. To this was added 0.2 g (10% w/w) of catalyst (5%Rhodium/Al₂O₃) and placed under hydrogen atmosphere. After 16 h ofstirring all starting material was consumed. The reaction mixture wasfiltered though a pad of celite and washed with additional amount ofmethanol and concentrated to get the desired product (1.96 g) in 98%yield. MS (ES) m/e 480.2 [M+H]⁺.

The acid (0.5 g) was suspended in dry acetonitrile (10 mL) and treatedwith 1.0M HCl (5.2 mL) in ether. The reaction stirred for 15 minutesthen concentrated to give pale yellow foam in quantitative yield. MS(ES) m/e 480.2 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.64 (t, 1H), 8.45(t, 1H), 7.27 (d, 1H), 7.15-7.04 (m, 4H), 5.86 (d, 1H), 4.20-4.03 (m,3H), 3.37-2.82 (m, 10H), 2.55-2.45 (m, 2H), 1.93 (d, 2H), 1.35 (s, 6H).

Example 13 Preparation of3-{2,3-Chloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester trifluoroacetate

The acid of Example 12 (2.0 g) was dissolved in absolute ethanol (50 mL)and catalytic amount of conc.sulfuric acid was added. The reaction wasstirred and heated to reflux overnight. Next day the reaction wasconcentrated and diluted with ethyl acetate and washed with 2.5N NaOH(2×20 mL), brine (20 mL) and dried over sodium sulfate. MS (ES) m/e 508[M+H]⁺.

The ethyl ester (33.7 g) was dissolved in dry acetonitrile and placedunder inert atmosphere. To this was added 6 mL of trifluoroacetic acidstirred for 15 minutes and concentrated to give thick pale yellow syrupin quantitative yield (41.2 g). MS (ES) m/e 508 [M+H]⁺. ¹H-NMR (400 MHz,DMSO-d₆) δ: 8.35 (brs, 2H), 7.31 (d, 1H), 7.20-7.08 (m, 5H), 5.91 (brs,1H), 4.20-4.02 (m, 5H), 3.27-3.20 (m, 1H), 3.09, 3.05 (dd, 1H), 2.95 (t,1H), 2.61-2.47 (m, 5H), 1.93 (d, 2H), 1.35 (s, 6H), 1.28 (d, 3H), 1.16(t, 3H).

Example 14 Preparation of3-{4-Fluoro-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester hydrochloride (a)(R)-2-(5-Bromo-2-fluoro-phenoxymethyl)-oxirane

A solution of the crude 5-bromo-2-fluorophenol (4.0 g) prepared usingliterature procedure [EP0238272] and (2R)-glycidyl3-nitrobenzenesulfonate (5.37 g) in dry acetone (175 mL) was treatedwith potassium carbonate (8.58 g) and refluxed under nitrogen for 12 h.The reaction was cooled, filtered and filtrate was concentrated in vacuoand the residue was flash chromatographed (20% ethyl acetate/hexanes) toyield the desired product (4.25 g) in 82% yield. ¹H NMR (400 MHz,CDCl₃): δ 7.15-6.96 (m, 3H), 4.33 and 4.30 (dd, 1H), 4.02 and 4.00 (dd,1H), 3.41-3.37 (m, 1H), 2.97 (m, 1H), 2.78 (m, 1H).

(b)(R)-1-(5-Bromo-2fluoro-phenoxy)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propan-2-ol

A mixture of the epoxide (3.0 g) and indanyl amine (2.24 g) were takenup in absolute ethanol (60 mL) and refluxed overnight. After all theepoxide was consumed the reaction was cooled and concentrated andpurified by flash chromatography (10% methanol/dichloromethane) to yield87% of the desired product (4.55 g). MS (ES) m/e 437 [M+H]⁺.

(c) (E)-3-{4-Fluoro-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-acrylic acid ethyl ester

A sealed tube was charged with a stir bar, the bromide (5.20 g) andpropionitrile (60 mL). To this was added Pd(OAc)₂ (0.54 g) and P(O-tol)₃(2.91 g), ethyl acrylate (1.95 mL) sequentially and deoxygenated thereaction by bubbling nitrogen for 15 minutes. The sealed tube was cappedtightly and immersed into a preheated (120° C.) oil bath. The reactionwas heated at this temperature for 12 h. Cool to ambient temperature andconcentrated under reduced pressure. The crude residue was purified byflash column chromatography eluting initially with 50% EtOAc in hexanesand 100% EtOAc. At this time the eluting solvent mixtures were switchedto 100% DCM, 5% MeOH in dichloromethane followed by 8% MeOH in DCM. Theproduct was collected and concentrated to get the desired product (4.81g) in 88% yield as pale yellow foam. MS (ES) m/e 556 [M+H]⁺.

(d) 3-{4-Fluoro-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl pent-4-enoic acid ethyl ester hydrochloride

The 250 ml round bottom flask was equipped with a magnetic stir bar,ethyl acrylate (3.2 g, 7 mmol), 100 ml of absolute ethanol. To this wasadded 0.32 grams (10% w/w) of catalyst (Pd/CaCO₃) and placed underhydrogen atmosphere. After 16 h of stirring all starting material wasconsumed. The reaction mixture was filtered through a pad of celite andwashed with additional amount of ethanol and concentrated to get thedesired product 7 (3.12 g, 97%). MS (ES) m/z 458 [M+H]⁺.

The ester 7 (0.5 g, 1 mmol) was suspended in dry acetonitrile (10 mL)and treated with 2.0M HCl (3 mL, 5 equiv.) in ether. The reactionmixture became homogeneous after few minutes then white solid crashedout. Reaction was stirred for additional 10 minutes upon which it wasfiltered and dried to get the desired salt (0.43 g, 80%). MS (ES) m/z458 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.56 (s, 1H), 8.45 (s, 1H),7.28-7.15 (m, 6H) 6.91-6.88 (m, 1H), 5.98 (d, 1H), 4.26 (brs, 1H),4.19-4.14 (m, 2H), 4.13 (q, 2H), 3.30-3.24 (m, 1H), 3.18 and 3.14 (dd,2H), 3.09-3.02 (m, 1H), 2.90 (t, 2H), 2.71-2.57 (m, 5H), 2.02 (d, 2H),1.45 (s, 6H), 1.28 (t, 3H).

Example 15 Preparation of3-{4-Fluoro-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid hydrochloride

A solution of ester of Example 14 (2.58 g, 5.6 mmol) in ethanol (250 ml)was treated with 2.5 N NaOH (10 mL, 4.5 eq.) and stirred at roomtemperature under argon overnight. The ethanol was removed in vacuo andthe aqueous layer was diluted with water (30 ml) and then extracted withether (3×100 ml). The aqueous layer was collected and the pH wasadjusted to pH 5 with conc.HCl while stirring. The precipitated whitesolid was collected by filtration and air dried to afford the titlecompound 8 (1.98 g, 81%). MS (ES) m/z 430 [M+H]⁺

The acid 8 (0.10 g, 0.23 mmol) was suspended in dry acetonitrile (5 mL)and treated with 2.0M HCl (1 mL, 5 equiv.) in ether. The reactionmixture became homogeneous after few minutes then white solid crashedout. Reaction was stirred for additional 10 minutes upon which it wasfiltered and dried to get the desired salt (96 mg, 89%). MS (ES) m/z 430[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.61 (t, 1H), 8.43 (t, 1H),7.20-7.07 (m, 6H), 6.84-6.81 (m, 1H), 5.91 (s, 1H), 4.20 (brs, 1H),4.12-4.07 (m, 2H), 3.22-3.17 (m, 1H), 3.11 and 3.07 (dd, 2H), 3.01-2.97(m, 1H), 2.79 (t, 2H), 2.62-2.49 (m, 5H), 1.95 d, 2H), 1.38 (s, 6H).

Example 16 Preparation of3-{2-Chloro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester hydrochloride (a)3-(2-Chloro-5-hydroxy-phenyl)-propionic acid ethyl ester

To a 0° C. solution of 3-(3-hydroxy-phenyl)-propionic acid ethyl ester(1.0 g, 5.15 mmol) in diethyl ether (50 ml) was added sulfuryl chloride(0.493 mL, 6.18 mmol). After 2.5 h at 0° C., the reaction was quenchedwith sat. sodium carbonate (50 ml). The aqueous layer was extracted withethyl acetate. The organic portions were combined and dried withmagnesium sulfate. The solvent was removed in vacuo to afford crudeproduct, which was purified by column chromatography (10% ethylacetate/hexanes). The title compound was obtained as colorless oil (0.73g, yield 62%): ¹H NMR (CDCl₃) δ 6.96 (d, J=10.1 Hz, 1H); 6.54 (d, J=2.97Hz, 1H); 6.46 (dd, J=8.6, 3.0 Hz, 1H); 3.96 (dd, J=12.5 5.3 Hz, 2H);2.82-2.78 (m, 2H); 1.08-1.00 (m, 3H).

(b)3-{2-Chloro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester hydrochloride

Utilizing the procedures described above in Examples 1a-b3-(2-chloro-5-hydroxy-phenyl)-propionic acid ethyl ester was convertedto the title compound LCMS (m/z) M+H=474.4

Example 17 Preparation of3-{2-Chloro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid hydrochloride

The ethyl ester of Example 16 was saponified to provide the titlecompound: ¹H NMR (DMSO) δ 8.78 (s, 1H); 8.46 (s, 1H); 7.36 (d, J=8.7 Hz,2H); 7.20-7.18 (m, 2H); 7.12-716 (m, 2H); 6.90 (s, 1H); 6.86 (d, J=3.0Hz, 1H); 4.02-3.98 (m, 2H); 3.36-3.32 (m, 2H); 3.12-3.04 (m, 2H);2.90-2.84 (m, 2H); 2.62-2.44 (m, 6H); 1.38 (s, 6H): LCMS (m/z)M+H=446/448.

Example 18 Preparation of3-{2,4-Dichloro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester

To a solution of3-{3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester (0.35 g, 0.683 mmol, obtained from3-(3-hydroxy-phenyl)-propionic acid ethyl ester by methods describedherein) in chloroform (6.8 mL) was added N-chlorosuccinimide (0.27 g,2.05 mmol) at RT. The reaction was heated to reflux overnight. Solventwas removed in vacuo, and the crude product was purified by reversephase HPLC (65% CH₃CN/H₂O with 0.1% TFA). Pure product was obtained aswhite solid (0.12 g, yield 30%): ¹H NMR (CDCl₃) δ 7.2 (s, 1H); 7.26 (s,1H); 7.18-7.12 (m, 4H); 6.86 (s, 1H); 4.51 (s, 1H); 4.28-4.18 (m, 2H);4.16-4.12 (m, 2H); 3.40 (m, 1H); 3.22-3.18 (m, 2H); 3.14 (dd, J=15, 7.6Hz, 2H); 3.00 (t, J=7.5 Hz, 2H); 2.26-2.22 (m, 2H); 2.60 (t, J=7.5 Hz,2H); 2.54 (m, 1H); 2.08 (m, 2H); 1.52 (s, 6H); 1.26 (t, J=7.1 Hz, 3H):LCMS (m/z) M+H=508/510/512.

Example 19 Preparation of5-{2,3-Dichloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pentanoicacid (a)(E)-3-{2,3-Dichloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pent-4-enoic acid ethyl ester

A 75 mL sealed tube was charged with a stir bar,(R)-1-(4-bromo-2,3-dichloro-phenoxy)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propan-2-olof Example 11c (2.0 g) and propionitrile (50 mL). To this was addedPd(OAc)₂ (0.09 g) and P(O-tol)₃ (0.5 g), ethyl 4-pentenoate (1.05 g) anddiisopropylethylamine (2.08 mL) sequentially and deoxygenated thereaction by bubbling nitrogen for 15 minutes. The sealed tube was cappedtightly and immersed into a preheated (120° C.) oilbath. The reactionwas heated at this temperature for 12 h. Cool to ambient temperature andconcentrated under reduced pressure. The crude residue was purified byflash column chromatography eluting initially with 50% EtoAc in hexanesand 100% EtoAc. At this time the eluting solvent mixtures were switchedto 100% dichloromethane, 5% MeOH in dichloromethane followed by 8% MeOHin dichloromethane. The product was collected and concentrated toprovide the title compound (2.0 g) in 92% yield as pale yellow foam. MS(ES) m/e 534 [M+H]⁺.

(b)(E)-3-{2,3-Dichloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pent-4-enoic acid

A solution of ester of Example 19a (2.0 g) in ethanol (25 mL) as treatedwith 2.5 N NaOH (6 mL) and stirred under nitrogen overnight. The ethanolwas evaporated and the aqueous layer was diluted with water (10 mL) andthen extracted with ether (3×100 mL). The pH of the aqueous layer wasadjusted to pH 5 with concentrated HCl and extracted withdichloromethane, dried and concentrated to give pale yellow foam in 81%yield (1.53 g). MS (ES) m/e 506 [M+H]⁺.

(c) 3-{2,3-Dichloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl pent-4-enoic acid trifluoroacetate

A 250 mL round bottom flask was equipped with a magnetic stir bar, theacid of Example 19b (1.0 g), 100 mL of absolute ethanol and 50 mL ofmethanol. To this was added 0.2 g (10% w/w) of catalyst (5%Rhodium/Al₂O₃) and placed under hydrogen atmosphere. After 16 h ofstirring all starting material was consumed. The reaction mixture wasfiltered though a pad of Celite and washed with additional amount ofmethanol and concentrated. The resulted pale yellow syrup was purifiedby HPLC (eluted with CH₃CN/H₂O containing 0.1% TFA) to produce thedesired product in 72% yield (0.88 g). MS (ES) m/e 508 [M+H]⁺. ¹H-NMR(400 MHz, DMSO-d₆) δ: 8.19 (brs, 2H), 7.14 (d, 1H), 7.03-6.92 (m, 5H),5.77 (brs, 1H), 4.05-3.91 (m, 2H), 3.13-3.05 (m, 2H), 2.97-2.88 (m, 4H),2.55-2.35 (m, 4H), 2.08 (t, 2H), 1.77 (d, 2H), 1.63-1.58 (m, 2H),1.37-1.35 (m, 2H), 1.20 (d, 6H).

Example 20 Preparation of3-{2,3-Dichloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl pent-4-enoic acid ethyl ester trifluoroacetate

The acid of Example 19 (0.5 g) was dissolved in absolute ethanol (10 mL)and catalytic amount of conc.sulfuric acid was added. The reaction wasstirred and heated to reflux overnight. Next day the reaction wasconcentrated and diluted with ethyl acetate and washed with 2.5N NaOH(2×20 mL), brine (20 mL) and dried over sodium sulfate. The crudemixture was purified by HPLC (eluted with CH₃CN/H₂O containing 0.1% TFA)to produce the desired product in 81% yield (0.43 g). MS (ES) m/e 536[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.35-8.48 (brs, 2H), 7.31-7.10 (m,6H), 4.17-4.01 (m, 5H), 3.26-3.05 (m, 4H), 2.69-2.50 (m, 7H), 2.32 (t,2H), 1.94 (d, 2H), 1.58-1.54 (t, 2H), 1.33 (s, 3H), 1.35 (s, 3H), 1.18(t, 3H).

Example 21 Preparation of3-{2,3-Dichloro-4-[2-(R)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(R)-methyl-propoxy]-phenyl propionic acid ethyl esterhydrochloride3-{2,3-Dichloro-4-[2-(S)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(S)-methyl-propoxy]-phenyl propionic acid ethyl esterhydrochloride3-{2,3-Dichloro-4-[2(-R)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(S)-methyl-propoxy]-phenyl propionic acid ethyl esterhydrochloride2,3-Dichloro-4-[2-(S)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(R)-methyl-propoxy]-phenyl propionic acid ethyl esterhydrochloride (a) 1-Bromo-2,3-dichloro-4-(1-methyl-allyloxy)-benzene

To a cold mixture of but-3-ene-1-ol (1.29 g) 4-bromo-2,3-dichlorophenol(4.35 g) was added triphenylphosphine (5.65 g) and DEAD (3.69 g)sequentially. Reaction was slowly warmed to room temperature whilestirring. After 12 h the reaction was concentrated and the crude residuewas purified by flash column chromatography eluting with EtOAc inhexanes to get the desired product (3.83 g) in 72% yield as pale yellowfoam. ¹H-NMR (400 MHz, CDCl₃) δ: 7.44 and 6.77 (ABq, 2H), 5.95-5.87 (m,1H), 5.31-5.20 (m, 2H), 4.81-4.78 (m, 1H), 1.52 (d, 3H).

(b) 2-[1-(4-Bromo-2,3-dichloro-phenoxy)-ethyl]-oxirane

1-Bromo-2,3-dichloro-4-(1-methyl-allyloxy)-benzene (2.5 g),1,1,1-trifluoroacetone (6.05 mL) and sodium bicarbonate (2.12 g) weretaken up in a solvent mixture of acetonitrile and water (2:1, 45 mL) andcooled to 0° C. Oxone (5.19 g) was added in three portions and thereaction was slowly warmed to room temperature. Upon completion thereaction was filtered and concentrated and re-dissolved in ethylacetate. This solution was washed with saturated NH₄Cl, brine and driedover sodium sulfate. Upon filtration, it was concentrated and purifiedby flash column chromatography eluting with EtOAc in hexanes to get thedesired product (2.39 g) in 91% yield as white solid. ¹H-NMR (400 MHz,CDCl₃) δ: 7.48 (d, 2H), 6.97 (d, 1H), 6.83 (d, 1H), 4.40-4.38 (m, 1H),4.15-4.08 (m, 1H), 3.25-3.21 (m, 1H), 3.18-3.16 (m, 1H), 2.89 (t, 1H),2.85-2.68 (m, 3H), 1.49-1.44 (m, 6H).

(c)3-(4-Bromo-2,3-dichloro-phenoxy)-(2-indan-2-yl-1,1-dimethyl-ethylamino)-butan-2-ol

A mixture of the epoxide (4.44 g) and indanyl amine (2.69 g) were takenup in absolute ethanol (16 mL) and refluxed overnight. After all theepoxide was consumed the reaction was cooled, concentrated and flashchromatographed (10% methanol/dichloromethane) to yield 93% of thedesired product (6.61 g). MS (ES) m/e 502.4 [M+H]⁺.

(d) (E)-3-{2,3-Dichloro-4-[2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1-methyl-propoxy]-phenyl}-acrylic acid ethyl ester

A 75 mL sealed tube was charged with a stir bar, the bromide of Example21c (5.0 g) and propionitrile (100 mL) this was added Pd(OAc)₂ (0.22 g)and P(O-tol)₃ (1.22 g) ethyl acrylate (2.17 mL) andN,N-diisopropylethylamine (7.10 mL) sequentially and deoxygenated thereaction by bubbling nitrogen for 15 minutes. The sealed tube was cappedtightly and immersed into a preheated (120° C.) oil bath. The reactionwas heated at this temperature for 12 h. Cool to ambient temperature andconcentrated under reduced pressure. The crude residue was purified byflash column chromatography eluting initially with 50% EtOAc in hexanesand 100% EtOAc. At this time the eluting solvent mixtures were switchedto 100% dichloromethane, 5% MeOH in dichloromethane followed by 8% MeOHin dichloromethane. The product was collected and concentrated toprovide the desired product (5.10 g) in 98% yield as pale yellow foam.MS (ES) m/e 520 [M+H]⁺.

(e) (E)-3-{2,3-Dichloro-4-[2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1-methyl-propoxy]-phenyl}-propoxy]-phenyl}-acrylic acid

A solution of ester of Example 21d (5.0 g) in ethanol (100 mL) wastreated with 2.5 N NaOH (16 mL) and stirred at room temperature underargon overnight. The ethanol was removed under pressure and the aqueouslayer was diluted with water (10 mL) and then extracted with ether(3×100 mL). The aqueous layer was collected and the pH was adjusted to 4with conc.HCl. The precipitated white solid was collected by filtrationand air dried to afford the diastereomeric mixtures in 77% yield (3.64g). MS (ES) m/e 492 [M+H]⁺.

(f) 3-{2,3-Dichloro-4-[2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1-methyl-propoxy]-phenyl propionic acid

The 250 mL round bottom flask was equipped with a magnetic stir bar, theacrylic acid of Example 21e (0.58 g) 20 mL of absolute ethanol. To thiswas added 0.2 g (10% w/w) of catalyst (5% Rhodium/Al₂O₃) and placedunder hydrogen atmosphere. After 48 h of stirring all starting materialwas consumed. The reaction mixture was filtered though a pad of celiteand washed with additional amount of methanol and concentrated to getthe desired product as a mixture of diastereomers (0.58 g). MS (ES) m/e494 [M+H]⁺.

(g) 3-{2,3-Dichloro-4-[2-(R)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(R)-methyl-propoxy]-phenyl propionic acid ethyl esterhydrochloride3-{2,3-Dichloro-4-[2-(S)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(S)-methyl-propoxy]-phenyl propionic acid ethyl esterhydrochloride3-{2,3-Dichloro-4-[2(-R)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(S)-methyl-propoxy]-phenyl propionic acid ethyl esterhydrochloride3-{2,3-Dichloro-4-[2-(S)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(R)-methyl-propoxy]-phenyl propionic acid ethyl esterhydrochloride

The acid of Example 20f (2.50 g) was dissolved in absolute ethanol andcatalytic amount of conc.sulfuric acid was added. The reaction wasstirred and heated to reflux overnight. The next day the reaction wasconcentrated and diluted with ethyl acetate and washed with 2.5N NaOH,brine and dried (Na₂SO₄). The crude residue was purified by flash columnchromatography eluting initially with 50% EtOAc in hexanes and 100%EtOAc. At this time the eluting solvent mixtures were switched to 100%dichloromethane, 5% MeOH in dichloromethane followed by 8% MeOH in DCM.The product was collected and concentrated to get the desired product(0.8 g) of pure product(s) and another 0.7 grams with 10% impurity. Thepure product containing all four diastereoisomers was seperated by HPLCto give 100-250 mgs of each individual diastereoisomer in greater than99% purity. MS (ES) m/e 522 [M+H]⁺.

Each pure stereoisomer was suspended in dry acetonitrile and treatedwith 1.0M HCl in ether. After 15 minutes reaction was concentrated toprovide the title compounds as pure distereomers: Each individualdiastereomer possessed a molecular weight by mass spectral analysiswhich was consistent with the molecular formula MS (ES) m/e 522 [M+H]⁺.

Example 22 Preparation of3-{2,3-Dichloro-4-[2-(R)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(R)-methyl-propoxy]-phenyl propionic acid hydrochloride3-{2,3-Dichloro-4-[2-(S)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(S)-methyl-propoxy]-phenyl propionic acid hydrochloride3-{2,3-Dichloro-4-[2(-R)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(S)-methyl-propoxy]-phenyl propionic acid hydrochloride3-{2,3-Dichloro-4-[2-(S)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(R)-methyl-propoxy]-phenyl propionic acid hydrochloride

Each of the individual diastereomeric esters of Example 21 weresaponified with aqueous NaOH and subsequently converted to thehydrochloric acid salt by treatment with hydrochloric acid in dryacetonitrile to provide the title compounds. Each individualdiastereomeric acid possessed a molecular weight by mass spectralanalysis which was consistent with the molecular formula: MS (ES) m/e494 [M+H]⁺.

Example 23 Preparation of3-{3-Chloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester

Following the general procedure of Example 1 a-b except substituting3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester forbromo-2,3-difluorophenol the title compound was produced.

Example 24 Preparation of3-{3-Chloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid

Following the general procedure of Example 1 c except substituting theester of Example 23 the title compound was produced.

Example 25 Preparation of3-{3-Bromo-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester

Following the general procedure of Example 1 a-b except substituting3-(3-bromo-4-hydroxy-phenyl)-propionic acid ethyl ester forbromo-2,3-difluorophenol the title compound was produced.

Example 26 Preparation of3-{3-Chloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl)}-propionicacid

Following the general procedure of Example 1 c except substituting theester of Example 25 the title compound was produced.

Example 27 Preparation of3-{3-[(R)-2-Hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester (a) 3-(3-Hydroxy-phenyl)-propionic acid ethyl ester

An ethanolic solution (250 mL) of 3-(3-Hydroxy-phenyl)-propionic acid(25 g, 100.4 mol) and concentrated sulfuric acid (3.0 mL) was heated toreflux for 2 hours and then at room temperature overnight. The solventwas removed by rotoevaporation, and the residue was brought up in ethylacetate. The organic portion was washed successively with 5% NaHCO₃ (2×)and brine, dried over MgSO₄, filtered and concentrated to a brown oil(30 g, quant). this material was used without further purification.

(b) 3-[3-((R)-1-Oxiranylmethoxy)-phenyl]-propionic acid ethyl ester

To an acetone solution (0.15 M, 170 mL) of3-(3-Hydroxy-phenyl)-propionic acid ethyl ester (5.0 g, 25.77 mmol) wasadded K₂CO₃ (10.69 g, 77.32 mmol), and the mixture was heated to refluxfor 30 min. After cooling this mixture to RT, (2R)-(−)-glycidyl3-nitrobenzenesulfonate (6.68 g, 25.77 mmol) was added, and theresulting mixture was heated to reflux overnight. After cooling to roomtemperature, the solids were removed by filtration and washed well withethyl acetate. The filtrate was concentrated and partitioned betweenethyl acetate and 1N HCl. The organic portion was washed successivelywith 5% NaHCO₃ and brine, dried (MgSO₄), filtered and concentrated to asolid. Purification by FCC (30% ethyl acetate/hexanes) gave the productas a white solid in 93% yield (6.0 g). LCMS (m/z) M+H: 187

(c)3-{3-[(R)-2-Hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester

An ethanolic solution (0.2 M, 100 mL) of the above-mentioned oxirane (5g, 20.0 mmol) and 2-indan-2-yl-1,1-dimethyl-ethylamine (free base, 3.78g, 20.0 mmol) was heated to reflux for 15 h. After solvent removal, thecrude reaction mixture was purified by FCC (2% to 5% CH₃OH/CH₂Cl₂) togive the title compound as a yellow oil in 85% yield (7.5 g).

LCMS (m/z) M+H: 440.

Example 28 Preparation of3-{3-[(R)-2-Hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid

To a solution of3-{3-[(R)-2-Hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester (1.3 g, 3.0 mmol) of Example 27 in ethanol (12 mL) andwater (3 mL) was added 2N NaOH (3 mL, 6.0 mmol). The solution stirred atroom temperature overnight. The ethanol was removed, and the residue waspartitioned between diethyl ether and water. The aqueous portion waswashed 3 times with diethyl ether and then adjusted to pH 5. The solidthat precipitated from the aqueous layer was isolated by filtration togive the pure zwitterion as a white solid.

To an acetonitrile suspension of the zwitterion product was added 2M HClin diethyl ether. The material briefly went into solution, and thenprecipitated as a white solid to give the title compound as the HClsalt, which was isolated by filtration and dried under vacuum (0.85 g,63%).

LCMS (m/z) M+H: 412.

Example 29 Preparation of3-{4-[(R)-2-Hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid

The 25 mL round bottom flask was equipped with a magnetic stir bar, thedichloro propionic acid (0.12 g, 0.25 mmoles), 3 mL of absolute ethanol.To this was added 0.012 grams (10% w/w) of catalyst (Pd/C) and placedunder hydrogen atmosphere. Stirring at room temperature tilldechlorination complete. The reaction mixture was filtered through a padof celite, washed with additional amount of ethanol and concentrated,purified by HPLC to yield TFA salt (36 mg). MS (ES) m/z 412 [M+H]⁺

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The above description fully discloses the invention including preferredembodiments thereof. Modifications and improvements of the embodimentsspecifically disclosed herein are within the scope of the followingclaims. Without further elaboration, it is believed that one skilled inthe area can, using the preceding description, utilize the presentinvention to its fullest extent. Therefore the Examples herein are to beconstrued as merely illustrative and not a limitation of the scope ofthe present invention in any way. The embodiments of the invention inwhich an exclusive property or privilege is claimed are defined asfollows.

What is claimed:
 1. A method of treating a disease or disordercharacterized by abnormal bone or mineral homeostasis, which comprisesthe administration to a subject in need of treatment thereof aneffective amount of a compound of formula (I):

wherein: R₁ and R₅ are independently selected from the group consistingof H and halogen; R₂, R₃ and R₄ are independently selected from thegroup consisting of H, halogen and J-K wherein: J is a covalent bond,alkylene or alkenyl; and K is selected from the group of CO₂R₈, whereinR₈ is H or alkyl; R₆ is selected from the group consisting of H andalkyl; and R₇ is selected from the group consisting of aryl, fused aryl,dihydro, tetrahydro fused aryl, and heteroaryl, unsubstituted orsubstituted with any substituent selected from the group consisting ofOH, halogen, C_(1-4 alkyl), C_(1-4alkoxy), C_(3-6 cycloalkyl), CF₃,OCF₃, CN and NO₂, or a pharmaceutically acceptable salt or complexthereof.
 2. A method according to claim 1, wherein the bone or mineraldisorder is selected from the group consisting of osteosarcoma,periodontal disease, fracture healing, osteoarthritis, rheumatoidarthritis, Paget's disease, humoral hypercalcemia malignancy, andosteoporosis.
 3. The method according to claim 1, wherein the compoundadministered is selected from the group consisting of:(E)-3-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-acrylicacid hydrochloride;3-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid hydrochloride;3-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester hydrochloride;(E)-3-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pent-4-enoicacid hydrochloride;5-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pentanoicacid hydrochloride;5-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pentanoicacid ethyl ester;3-{4-Bromo-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester hydrochloride;3-{4-Bromo-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid hydrochloride;3-{4-Fluoro-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester hydrochloride;3-{4-Fluoro-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid hydrochloride;3-{2-Chloro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester hydrochloride;3-{2-Chloro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid hydrochloride;3-{2,4-Dichloro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester;3-{3-[(R)-2-Hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester; and3-{3-[(R)-2-Hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid.
 4. The method according to claim 1, wherein the compoundadministered is selected from the group consisting of:3-{2,3-Difluoro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid hydrochloride;3-{2,3-Difluoro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester hydrochloride;(E)-3-{2,3-Dichloro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-acrylicacid hydrochloride;3-{2,3-Chloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid hydrochloride;3-{2,3-Chloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester trifluoroacetate;5-{2,3-Dichloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pentanoicacid trifluoroacetate;5-{2,3-Dichloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pentanoicacid ethyl ester trifluoroacetate;3-{2,3-Dichloro-4-[2-(R)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(R)-methyl-propoxy]-phenyl propionic acid ethyl esterhydrochloride;3-{2,3-Dichloro-4-[2-(S)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(S)-methyl-propoxy]-phenyl propionic acid ethyl esterhydrochloride;3-{2,3-Dichloro-4-[2-(R)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(S)-methyl-propoxy]-phenyl propionic acid ethyl esterhydrochloride;3-{2,3-Dichloro-4-[2-(S)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(R)-methyl-propoxy]-phenyl propionic acid ethyl esterhydrochloride;3-{2,3-Dichloro-4-[2-(R)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(R)-methyl-propoxy]-phenyl propionic acid hydrochloride;3-{2,3-Dichloro-4-[2-(S)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(S)-methyl-propoxy]-phenyl propionic acid hydrochloride;3-{2,3-Dichloro-4-[2(-R)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(S)-methyl-propoxy]-phenyl propionic acid hydrochloride;3-{2,3-Dichloro-4-[2-(S)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(R)-methyl-propoxy]-phenyl propionic acid hydrochloride;3-{3-Chloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester;3-{3-Chloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid;3-{3-Bromo-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester;3-{3-Bromo-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid; and3-{4-[(R)-2-Hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid.
 5. The method according to claim 4, wherein the compoundadministered is selected from the group consisting of:3-{2,3-Difluoro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid hydrochloride;3-{2,3-Difluoro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester hydrochloride;(E)-3-{2,3-Dichloro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-acrylicacid hydrochloride;3-{2,3-Chloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid hydrochloride;3-{2,3-Dichloro-4-[2-(R)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(R)-methyl-propoxy]-phenyl propionic acid ethyl esterhydrochloride;3-{2,3-Dichloro-4-[2-(S)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(S)-methyl-propoxy]-phenyl propionic acid ethyl esterhydrochloride;3-{2,3-Dichloro-4-[2-(R)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(S)-methyl-propoxy]-phenyl propionic acid ethyl esterhydrochloride;3-{2,3-Dichloro-4-[2-(S)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(R)-methyl-propoxy]-phenyl propionic acid ethyl esterhydrochloride;3-{2,3-Dichloro-4-[2-(R)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(R)-methyl-propoxy]-phenyl propionic acid hydrochloride;3-{2,3-Dichloro-4-[2-(S)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(S)-methyl-propoxy]-phenyl propionic acid hydrochloride;3-{2,3-Dichloro-4-[2(-R)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(S)-methyl-propoxy]-phenyl propionic acid hydrochloride;3-{2,3-Dichloro-4-[2-(S)-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-1(R)-methyl-propoxy]-phenyl propionic acid hydrochloride;3-{3-Chloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester;3-{3-Chloro-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid;3-{3-Bromo-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester;3-{3-Bromo-4-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid; and3-{4-[(R)-2-Hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid.
 6. The method according to claim 1, wherein the compoundadministered is3-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid.
 7. The method according to claim 1, wherein the compoundadministered is a pharmaceutically acceptable salt of the compound3-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid.
 8. The method according to claim 1, wherein the compoundadministered is3-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid hydrochloride.
 9. The method according to claim 1, wherein thecompound administered is3-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester hydrochloride.
 10. The method according to claim 1,wherein the compound administered is a pharmaceutically acceptable saltof the compound3-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester hydrochloride.
 11. The method according to claim 1,wherein the compound administered is3-{3,4-Difluoro-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionicacid ethyl ester hydrochloride.